Metabolic functions flavin oxidases

Oxidation is by far the most important Phase I metabolic reaction. One of the main enzyme systems involved in the oxidation of xenobiotics appears to be the so called mixed function oxidases or monooxygenases, which are found mainly in the smooth endoplasmic reticulum of the liver but also occur, to a lesser extent, in other tissues. These enzymes tend to be nonspecific, catalysing the metabolism of a wide variety of compounds (Table 9.2). Two common mixed function oxidase systems are the cytochrome P-450 (CYP-450) and the flavin monoxygenase (FMO) systems (Appendix 12). The overall oxidations of these systems take place in a series of oxidative and reductive steps, each step being catalysed by a specific enzyme. Many of these steps require the presence of molecular oxygen and either NADH or NADPH as co-enzymes. 

The flavin-dependent mixed-function oxidases include amine N-oxidases and a variety of S-oxidases. They provide an alternative to cytochrome P450-dependent enzymes in the metabolism of xenobiotics. 

Fig. 40.5. Extensive metabolism of ketoconazole involving hydrolysis of the N-acetyl by a deacetylase. The oxidation reactions are catalyzed by CYP3A4 and a flavin-linked mixed-function oxidase. All metabolites are inactive.

An important group of mixed function oxidases which occur in all types of organism and which are critical in the metabolism of the aromatic amino adds and other aromatic substrates are the aromatic hydroxylases. Their mode of action, the overall stoichiometry of which is represented in the sequence below, results in the introduction of a phenolic hydroxyl group in an aromatic ring system and has been the subject of intensive study. Pyridine and flavin nucleotides, cytochromes, metals (Fe, Cu), ascorbate and pteridine derivatives (H2X) may serve as electron donors. Most, but not all, of these en2yme reactions require transition metal ions for full activity. 

Monoamine oxidases (MAOs, EC 1.4.3.4) are a family of flavin-dependent metabolic enzymes that catalyze the oxidative deamination of biogenic and xenobi-otic amines. They play an important role in motor and mood control, as well as in the regulation of motivation and other brain functions. Two isoenzymes, MAO-A and -B, are distinguishable on the basis of their in vitro substrate specificity and inhibitor sensitivity [1]. MAO-A has a higher affinity for 5-HT, and to lesser extent, for noradrenaline and dopamine. It is inhibited by low concentrations of clorgyline, whereas MAO-B is more specific toward benzylamine, 2-phenylethylamine, and is inhibited by selegiline (Deprenyl) [2,3]. 

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